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NVP-HSP990 is an orally bioavailable inhibitor of human heat-shock protein 90 (Hsp90) with IC50 values of 0.6, 0.8, and 8.5 nM for Hsp90α, Hsp90β, and Grp94, respectively. NVP-HSP990 has potential antineoplastic activity.
In vitro, NVP-HSP990 exhibits single digit nanomolar IC(50) values on three of the Hsp90 isoforms (Hsp90α, Hsp90β, and GRP94) and 320 nanomolar IC(50) value on the fourth (TRAP-1), with selectivity against unrelated enzymes, receptors, and kinases. In c-Met amplified GTL-16 gastric tumor cells, NVP-HSP990 dissociated the Hsp90-p23 complex, depleted client protein c-Met, and induced Hsp70. NVP-HSP990 potently inhibited the growth of human cell lines and primary patient samples from a variety of tumor types.
In vivo, NVP-HSP990 exhibits drug-like pharmaceutical and pharmacologic properties with high oral bioavailability. In the GTL-16 xenograft model, a single oral administration of 15 mg/kg of NVP-HSP990 induced sustained downregulation of c-Met and upregulation of Hsp70. In repeat dosing studies, NVP-HSP990 treatment resulted in tumor growth inhibition of GTL-16 and other human tumor xenograft models driven by well-defined oncogenic Hsp90 client proteins. On the basis of its pharmacologic profile and broad-spectrum antitumor activities, clinical trials have been initiated to evaluate NVP-HSP990 in advanced solid tumors.
Patent: US20230218577A1 2023 Jul.
Use of heat shock protein inhibitors for the treatment of neurodevelopmental disorders
NVP-HSP990 purchased from AbMole
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Source | Mol Cancer Ther (2012). Figure 1. NVP-HSP990 |
| Method | immunoprecipitation | |
| Cell Lines | GTL-16 cell line | |
| Concentrations | 250 nmol/L | |
| Incubation Time | 72 h | |
| Results | NVP-HSP990 is based on a 2-amino-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one scaffold, which is structurally distinct from other known Hsp90 inhibitors. Acocrystal structure solved to 1.5A resolution (manuscript in preparation) shows that NVP-HSP990 binds to the Nterminal ATP-binding domain of Hsp90. |
| Cell Experiment | |
|---|---|
| Cell lines | GTL-16, BT-474, A549, NCI-H1975 and MV4;11 cell lines |
| Preparation method | Cell proliferation and apoptosis assays Cells were treated with NVP-HSP990 or 17-AAG for 72 hours, and cell viability was determined by CellTiter-Glo Luminescent Cell Viability assay from Promega. Soft agar clonogenic assays with primary human tumors were conducted at Oncotest GmbH |
| Concentrations | 0~1000nM |
| Incubation time | 72 h |
| Animal Experiment | |
|---|---|
| Animal models | Human tumor xenograft models GTL-16, NCI-H1975, BT474, and MV4;11 |
| Formulation | 100% polyethylene glycol (PEG400) |
| Dosages | a single dose of 15 mg/kg |
| Administration | orally |
| Molecular Weight | 379.39 |
| Formula | C20H18FN5O2 |
| CAS Number | 934343-74-5 |
| Solubility (25°C) | DMSO 33 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
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| Hsp70-derived octapeptide
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